In triple negative breast cancer (TNBC), a tumor type that may be amenable to immune-based treatment, the biology of malignant cells in metastases drives mortality, rather than the biology of primary tumors. The realization that only about a fifth of patients really respond to immunotherapies suggests that more effort should be dedicated to understanding basic mechanism in the tumor microenvironment. Metabolic programs in both primary tumor and distant metastasis affect responsiveness to immunotherapy, but many important molecular switches of metabolism remain unexplored. The BET bromodomain proteins, comprising BRD2, BRD3 and BRD4 in somatic cells, are new critical regulators of metabolism and could be important targets in immunotherapy for TNBC. These transcriptional co-regulators are well known players in tumor cell prolifer- ation, but are only recently identified as critical for metabolism and metastasis. As we show here, individual BET proteins also control PD-L1 expression, central to immunotherapy. Small molecule pan-BET inhibitors (BETi), such as JQ1, show promise in several pre-clinical cancer models. Manipulation of individual BET proteins also increases fatty acid oxidation by transcriptional upregulation of metabolic genes and transacti- vates PPAR? target genes like PGC-1?, in ways that drive TNBC metastasis. Metabolic reprogramming is of interest, and Type 2 diabetes is a useful place to start. These mechanisms are critically important in metabolism of the TNBC microenvironment. Our preliminary data show that BRD2 and BRD4 oppose each other in metabolic functions: BRD2 co-represses PPAR? target genes and OXPHOS gene transcription, but BRD4 opposes glycolytic metabolism in TNBC. This suggests that properly selective BET inhibition could improve efficacy of immunotherapies. Our long term goal is to understand how BET bromodomain proteins reprogram metabolism to regulate progression and metastasis in TNBC, and immunotherapy responses. The objective here is to resolve the individual functions of each BET family member with selective knockdown and next-generation BETi, to define gene networks that regulate metabolism, metastasis and checkpoint function. The central hypothesis is that BET proteins control a metabolic switch in TNBC metabolism that is critical for metastasis, and can be reprogrammed for immunotherapy benefit. Strong preliminary data support three Specific Aims: 1. Determine how BET proteins control metabolic plasticity to drive progression of TNBC. 2. Determine how BET proteins regulate breast tumor immune escape through the PD-1/PD-L1 axis. 3. Determine how BET protein-regulated metabolic plasticity facilitates anti-PD-1/PD-L1 strategies. We will undertake an observational study of TNBC patients with and without Type 2 diabetes and metformin treatment. We expect to find that a BET protein metabolic switch regulates progression and metastases in TNBC, coupling metabolic reprogramming to checkpoint function. These insights will help tailor next generation BETi to maximize therapeutic efficacy of immunotherapy combinations and minimize metastasis risk in TNBC.